KR20090107956A - Pharmaceutical formulation - Google Patents

Abstract

PURPOSE: A pharmaceutical formulation is provided to uniformly maintain blood pressure during risk time of complication and used for suppressing blood pressure. CONSTITUTION: A pharmaceutical formulation contains an immediate release compartment and extended release compartment. The immediate release compartment contains a valsartan as a pharmacologically active ingredient and its pharmaceutically acceptable salt or its isomer. The extended release compartment contains an amlodipine as a pharmacologically active ingredient and pharmaceutically acceptable salt, or its isomer.

Description

Pharmaceutical Formulations

The present invention provides controlled release of amlodipine, pharmaceutically acceptable salts thereof, or isomers thereof (hereinafter 'amlodipine') and valsartan, pharmaceutically acceptable salts thereof, or isomers thereof (hereafter `` valsartan ''). It relates to a pharmaceutical formulation.

The present invention relates to a technology for formulating a functional combination that can suppress the decrease in drug efficacy due to drug interactions and prevent side effects from occurring when two drugs are simultaneously administered.

All drugs should be carefully reviewed for the characteristics of drug transporters, metabolic enzymes, and genes involved in the absorption, metabolism, distribution, drug expression and excretion of individual drugs when two or more components are taken. By determining the dissolution order and time difference of the ingredients and maintaining the time difference of absorption, it is possible to minimize the mutual antagonism between the drugs in the body. As a result, it is possible to reduce side effects and enhance the efficacy of drug combination. Is true

More specifically, the drug passes through the barrier in the first stage, enters the liver in the second stage, metabolizes and activates in the liver cells in the third stage, and the biliary tract in the fourth stage. Efflux transporters, influx transporters, and metabolic enzymes that absorb, metabolize, and excrete drugs everywhere, such as when exiting cells, exist everywhere.

However, depending on the type of drug, it may also inhibit the action of these transporters, enzymes and genes.

Therefore, when two drugs pass through each step at the same time, one component may interfere with the absorption, distribution, and metabolism of the other, thereby reducing the efficacy or increasing the side effects. Therefore, one component must be passed first, and the other component must be passed at a time difference to eliminate drug interaction.

There are currently 300 such transporters, 500 metabolic enzymes, and 57 genes. Soon, gene genome analysis will find transporters and enzymes for all drugs.

Therefore, it is impossible to claim that there is no interaction between two or more drugs because it is a private example that any drug whose metabolic enzyme or transporter is currently unknown will be discovered soon. Therefore, even if a drug of two components for which metabolic enzymes or transporters are not known, it is reasonable to absorb it with a dissolution time difference between the two components.

Background of the Invention The purpose of the present invention is to determine the dissolution order and maintain the time difference between the two components with a certain antagonistic interaction between the two components for the purpose of realizing the ideal combination method when all the drugs are heterogeneously administered. It is absorbed to enable functional combinations that maximize the efficacy and minimize side effects.

Examples of transporters and drug metabolizing enzymes that have been tested or reviewed for the preparation of the functional combination of the present invention are as follows.

1) Efflux Transporter: P-glycoprotein (P-gp), Multidrug resistance (MDR), Multidrug resistance associated protein (MRP)

2) Influx Transporter: Organic anion transport protein (OATP), Sodium taurocholate cotransporting polypeptide (NTCP), Organic cation transporter (OCT)

3) drug metabolism: Cytochrome P450 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 3A4 / 5

4) Other metabolic enzymes: Uridine-5-phophate-glucuronosyltransferase (UDP-gt), Sulfatase, Sulfotransferase (1a1, 2a1, 1e1)

5) Nucleic Receptor: Pregnane-X-Receptor (PXR), Constitutive Androstane Receptor (CAR)

Hypertension is the most common disease among chronic circulatory diseases, and the frequency of occurrence is increasing recently. Hypertension can cause fatal complications such as stroke, heart failure, and coronary artery disease, even though there are relatively no apparent symptoms in patients with severe severity.

Hypertension is divided into essential hypertension (primary hypertension) with no apparent cause and secondary hypertension (secondary hypertension) with pronounced causative disease. Primary hypertension accounts for more than 85% to 90% of patients with hypertension and has a strong genetic predisposition, but no clear cause is known. On the other hand, secondary hypertension is caused by various causes such as kidney disease, renal endocrine disease, and abnormal secretion of hormones, and is often caused by two or more duplicate causes in the same patient.

In order to successfully lower the blood pressure of hypertension caused by various causes, a combination prescription of anti-pressure drugs has been required.

In summary, the need for a combination regimen as a guideline for the treatment of hypertension is as follows [J. Hum. Hypertens 1995: 33-36.

1) Even in the same patient, a variety of causes are causing hypertension.

2) A single agent cannot control all of the various conditions.

3) The effect of a single agent is effective for up to 50% of prescription patients.

4) The effectiveness of the combination is effective for more than 80% of the prescribed patients.

5) In particular, for high blood pressure in people with complications such as diabetes, a single agent may not be able to achieve the desired anti-pressure effect, and it is more difficult to prevent complications.

6) If the use of a single low-dose did not have an effect, increasing the dose often increases only the side effects, but the combination can reduce these side effects.

7) Combination drugs can eliminate various causes and prevent complications and counteract side effects by combining pharmacological groups with different pharmacological effects. Is the best treatment, the American Heart Association emphasizes.

In particular, patients with high blood pressure who have complications should lower their blood pressure than those with high blood pressure without complications. In this case, a combination prescription is essential. The use of a single agent is effective for only 26% of patients, but combination prescriptions can help prevent complications by maintaining targeted blood pressure for as many as 74% of patients [Hypertension Optimal Treatment, United Kingdom Prospective Diabetes Study, Large clinical trials].

The U.S. FDA has recognized the need for a combination formulation under the so-called Fixed-dose Combination Therapy for more than 30 years.The fixed-rate combination principle is a combination of drugs with different pharmacological actions. It is a principle that the compound should be combined in the same amount as when prescribed.This is called a fixed ratio combination, and as long as the efficacy and safety of a single formulation are already recognized and the combination is prescribed by the prescriptions, these combinations are separate experiments. Without a license.

10) It is well known that fixed-rate complex antipressants have a lowering of blood pressure than single agents.

11) Since the dose of individual components is not increased, the occurrence of side effects of the individual components can be significantly prevented.

12) Many of the side effects of anticompressants are adverse effects on the circulatory system. Therefore, in many cases, the side effects of each other are canceled out by combining the components having different pharmacology.

13) Combination formulations make it easier for patients to comply with medications, reducing the wasted time on prescription medications as the elderly population grows.

14) Combination formulations can reduce the risk of developing circulatory complications, thereby reducing long-term prevention costs.

15) It is possible to reduce the packaging cost of maintaining a single formulation and reduce the time for dispensing of high-quality manpower.

As the above-mentioned pharmacologically active ingredient effective in hypertension of multifactorial and polymorphism, calcium channel blocker, angiotensin II receptor blocker renin blocker, beta adrenergic blocker, angiotensin converting enzyme inhibitor, diuretic agent, etc., depending on the similarity or mechanism of the chemical structure Can be mentioned.

Amlodipine in dihydropyridine-based calcium channel blocker [Chemical Name: 3-ethyl-5-methyl2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methyl -3,5-pyridinedicarboxylate] is a long-acting calcium channel blocker that shows activity over a long period of time. Amlodipine relaxes arterial smooth muscle and decreases blood pressure. Since it has a weak effect on most venous blood vessels, it has no effect on full heart load, dilates coronary artery, reduces coronary resistance, and increases coronary blood flow. The effectiveness and safety of amlodipine is also evidenced by the fact that it is the world's No. 1 prescription for the treatment of hypertension (European Patent Publication No. 89,167 and U.S. Patent No. 4,572,909, U.S. Patent No. 4,879,303, U.S. Patent 5,115,120).

Valsartan in angiotensin II receptor blocker (ARB) [N- (1-oxopentyl) -N-[[2 '-(1H-tetrazol-5-yl) [biphenyl] -4-yl] methyl] -L-valine] is an antihypertensive agent that relaxes blood vessels by blocking aldosterone action, which blocks the action of vasoconstrictor and increases the angiotensin II, a blood pressure raising substance. , Left ventricular hypertrophy, vascular hypertrophy, atherosclerosis, renal failure, stroke and the like (US Patent No. 5,399,578).

ARB drugs lower blood pressure, prevent and treat heart failure, arrhythmias after myocardial infarction, prevent and treat diabetic complications, prevent and treat renal failure, prevent and treat stroke, antiplatelet action, prevent atherosclerosis, inhibit aldosterone harmful effects, metabolism It is a drug that exhibits a wide range of actions, such as relieving the influence of syndrome and preventing the serial exacerbation of circulatory diseases. [Clin, Exp. Hypertens., Vol. 20 (1998), p. 205-221, J. Hypertens., Vol. 13 (8) (1995), p. 891-899, Kidney Int., Vol. 57 (2) (2000), p. 601-606, Am. J. Hypertens., Vol. 10 (12PT2) Suppl. (1997), p. 325-331, Circulation, vol. 101 (14) (2000), p. 1653-1659, J. Hypertension., Vol 17 (7) (1999), p.907-716, Circulation, vol. 101 (2000), p.2349].

Valsartan, one of the ARBs, has a strong blood pressure lowering effect from midnight to early morning when RAAS (Renin and angiotensin system) works strongly [J. Hypertens, 2005; 23: 1913-1922, Hypertension, 2003; 42: 283-290, Chronobiol. Int. 2005; 22: 755-776], amlodipine, one of dihydropyridine-based calcium channel blockers, is a drug that regulates the blood pressure increase caused by stressful vasospasm after waking up [Clin Invest 72: 864-869].

Valsartan and amlodipine have different mechanisms for lowering blood pressure and different time slots for optimal effects. Thus, a combination of two different classes of ingredients in patients with a single anti-hypertensive effect can provide synergistic antihypertensive effects. In addition, ARB is a potent potassium preparation for the properties of dihydropyridine-based calcium channel blockers that lose potassium ions. Combining the two ingredients is complementary, as it suppresses losses.

Before and after 60 years of age, systolic blood pressure is high, and diastolic blood pressure is relatively low, and systolic hypertension appears. This is called senile hypertension. This is because the hypertension patients with aging lower the renal function, so the secretion of angiotensin II, a blood pressure raising factor, increases blood pressure.

In the case of senile hypertension, it is difficult to lower the systolic blood pressure to the desired level with a single hypertension drug. Therefore, a combined regimen of hypertension drugs is needed more and in general, angiotensin II receptor blockers (ARBs) are recommended to be added to the primary treatment of hypertension therapy (WHO / ISH guidelines, 1999).

In many large clinical trials (LIFE, SCOPE, VALUE, etc.), ARB preparations have been shown to suppress circulatory complications and the development of diabetes in hypertensive patients of various conditions, increasing ARB combination therapy, especially monotherapy in the treatment of hypertension. Combination therapy with ARB and dihydropyridine calcium channel blocker formulations has been standardized in cases of zero blood pressure control failure.

As described above, due to the wide range of indications, a combination prescription of dihydropyridine-based calcium channel blocker and ARB has been attempted worldwide. The main contents are as follows.

U.S. Patent No. 20050209288 provides the same effect when combined with ARB preparations such as (S) amlodipine and valsartan (US Pat. No. 5,591,762) while reducing the dosage of the preparation than when using each alone. It is disclosed that there is.

Korean Patent Laid-Open Publication No. 2005-53690 mentions the necessity of a combination regimen in which a single agent is simultaneously administered, but it does not disclose a combination formulation for effective cardiovascular disease treatment.

Korean Patent Laid-Open Publication No. 2004-0078140 discloses the composition and therapeutic effect of an antihypertensive combination of an ARB formulation of valsartan and a calcium channel blocker, but it relates to a simple combination formulation without considering the metabolism of the drug.

Korean Patent Laid-Open Publication No. 1993-0701810 relates to a method of treating hypertension by combining angiotensin II receptor antagonist with a diuretic, calcium channel blocker, beta adrenergic blocker, renin inhibitor, or angiotensin converting enzyme inhibitor. Only the formulation possibilities for agents commonly used in cardiovascular diseases are disclosed without consideration.

WO 2004/067003 discloses calcium antagonists selected from angiotensin II receptor antagonists and 1,4-dihydropyridine-based compounds for the prevention and / or treatment of atherosclerosis, hypertension, heart disease, kidney disease or cerebrovascular disease. The present invention relates to a complex preparation containing the active ingredient, but it relates to a technique of simply combining various drugs commonly used for cardiovascular diseases.

International Publication No. 2007/001066 discloses pharmaceutical preparations based on angiotensin II receptor antagonists and calcium channel blockers and containing one or more substances selected from hydrophilic polymers, acidic substances and glidants as excipients, which improve solubility. A simple combination formulation with an excipient in addition to the angiotensin II receptor antagonist and calcium channel blocker for this purpose. As mentioned above, the prior documents only disclose a simple combination or simple combination formulation of valsartan and amlodipine, but no combination formulation for showing the optimal effect of valsartan and amlodipine has been disclosed.

Therefore, the present inventors have studied intensively the pharmacological action of valsartan and amlodipine, especially their drug metabolism, interactions and side effects, so that valsartan is pre-released and amlodipine is delayed in the combination preparation containing valsartan and amlodipine. By minimizing side effects due to the drug metabolism interaction of valsartan and amlodipine in the subject by controlling, it was found that these drugs exhibit the optimal effect to complete the pharmaceutical formulation of the present invention.

The present invention is to provide a pharmaceutical formulation that is controlled release at the time when the pharmacologically active ingredients, amlodipine and valsartan, can optimally function, respectively, and exhibit maximum effects in the treatment of cardiovascular diseases, hypertension and prevention of complications.

The present invention relates to a controlled release pharmaceutical formulation comprising a prior release compartment comprising valsartan as a pharmacologically active ingredient, and a delayed release compartment comprising amlodipine as a pharmacologically active ingredient.

Hereinafter will be described in more detail for the pre-release and delayed-release compartment of the pharmaceutical formulation of the present invention.

1.Preventive compartment

Pre-release compartment refers to the compartment that is released before the delayed-release compartment in the pharmaceutical formulation of the present invention.

The prior release compartment comprises (1) valsartan, a pharmaceutically acceptable salt thereof, or an isomer thereof (hereinafter 'valsartan') as a pharmacologically active ingredient, and (2) a pharmaceutically acceptable additive as necessary. It may further comprise.

(1) pharmacologically active ingredients

Prerelease compartments include valsartan, pharmaceutically acceptable salts thereof, and / or isomers thereof as pharmacologically active ingredients.

Valsartan, the active ingredient in the prior release compartment, comprises about 1-800 mg, preferably about 20-640 mg, in a single formulation, which is the reference dose per day for adults (65-75 kg adult male).

The valsartan of the prior-release compartment is released more than 85% of the total amount of valsartan within 1 hour after the start of its release, so that the desired drug can be rapidly generated.

(2) pharmaceutically acceptable additives

Pre-release compartments may also be formulated to include additives such as pharmaceutically acceptable diluents, binders, disintegrants, stabilizers, pH adjusting agents, dissolution aids, lubricants, surfactants, and the like without departing from the effects of the present invention.

The diluent may be starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, dicalcium phosphate, or a mixture thereof.

The binder is starch, microcrystalline cellulose, highly dispersible silica, mannitol, sucrose, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, natural gum, synthetic gum, copovidone, gelatin Or mixtures thereof.

The disintegrant may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch, microcrystalline crystalline cellulose, hydroxypropyl cellulose or carboxymethyl such as bentonite, montmorillonite, or veegum. Cellulose, such as cellulose Sodium alginate, Alginate, etc. Crosslinked cellulose, such as croscarmellose sodium Crosslinked polymer, such as guar gum and xanthan gum Crosslinked polymer, such as polyvinylpyrrolidone (crospovidone) Sodium bicarbonate and citric acid Effervescent preparations, such as these, or a mixture thereof can be used.

The stabilizer may be an alkali metal salt, a salt of alkaline earth metal, or an alkalizing agent which is a mixture thereof, and preferably calcium carbonate, sodium carbonate, sodium bicarbonate, magnesium oxide, magnesium carbonate, sodium citrate, or the like. Ascorbic acid, citric acid, butylated hydroxy anisole, butylated hydroxy toluene and tocopherol derivatives may also be used.

The pH adjusting agent may be an acidifying agent such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid and a basicizing agent such as precipitated calcium carbonate, aqueous ammonia, meglumine and the like.

The dissolution aid can be used polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, docusate sodium and the like.

The lubricant is talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostearate, glyceryl Palmitostearate or polyethylene glycol can be used.

As the surfactant, sodium lauryl sulfate, cremophore, poloxamer, docusate, pharmaceutically acceptable docusate salt, and the like can be used.

In addition, the formulation of the present invention may be formulated using various pharmaceutically acceptable additives selected from colorants and flavors, and the additives usable in the present invention are not limited to the above additives. The additives may be formulated to contain a range of usual doses by selection.

2. Delayed release block

Delayed-release compartment refers to a compartment that is released after a certain time after release of the prior release compartment in the pharmaceutical formulation of the present invention.

Delayed-release compartments include (1) amlodipine, a pharmaceutically acceptable salt thereof, or an isomer thereof (hereinafter 'amlodipine') as a pharmacologically active ingredient; (2-1) release controlling substance or (2-2) osmotic pressure control agent and semipermeable coating base, and (3) pharmaceutically acceptable additives as necessary.

(1) pharmacologically active ingredients

Delayed-release compartments include amlodipine, pharmaceutically acceptable salts thereof, and / or isomers thereof as pharmacologically active ingredients.

Amlodipine, the active ingredient in the delayed-release compartment, comprises about 1-40 mg, preferably about 2-20 mg, in a single formulation, which is the reference dose for an adult per day (65-75 kg adult male).

The amlodipine in the delayed-release compartment is released after a certain delay time, preferably 1 hour to 4 hours, more preferably 1 hour to 2 hours after the release of valsartan is initiated, thereby producing a desired drug. The release of amlodipine after a certain delay means that no amlodipine is released at all or less than 20% during the delay.

(2-1) Release Control Substances

The delayed-release compartment in the pharmaceutical formulation of the present invention comprises at least one release controlling substance selected from the group consisting of enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic polymers, and mixtures thereof for controlling the release of pharmacologically active ingredients. Include.

The release controlling substance comprises 0.1 to 100 parts by weight, preferably 1 to 50 parts by weight, based on 1 part by weight of amlodipine. If the release controlling substance is less than 0.1 parts by weight, it is difficult to have a sufficient delay time, and if it exceeds 100 parts by weight, the release of the drug does not occur or becomes longer than 9 hours of the delay time.

The enteric polymer refers to a polymer which is insoluble or stable under acidic conditions of less than pH 5, and is dissolved or decomposed under specific pH conditions of pH 5 or higher. The enteric polymer that can be used in the present invention is selected from the group consisting of enteric cellulose derivatives, enteric acrylic acid copolymers, enteric maleic acid copolymers, enteric polyvinyl derivatives, and mixtures thereof, wherein the enteric cellulose derivative is hydroxypropylmethylcellulose. Acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethyl ethyl At least one enteric acrylic acid system selected from cellulose, ethyl hydroxyethyl cellulose phthalate, and methyl hydroxyethyl cellulose Polymers include styrene-acrylic acid copolymers, methyl acrylate-acrylic acid copolymers, methyl methacrylate acrylic acid copolymers (e.g., acrylics (Eryl-eze, Colorcon, USA)), butyl-styrene-acrylic acid copolymers, methacrylic acid Methyl methacrylate copolymer (e.g. Eudragit L 100, Eudragit S, Degussa), methacrylic acid-ethyl acrylate copolymer (e.g. Eudragit L 100-55, Degussa), and acrylic acid The at least one enteric maleic acid copolymer selected from methyl-methacrylic acid-octyl acrylate copolymer is vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinyl methyl ether-maleic acid Anhydride copolymer, ethylene-maleic anhydride copolymer, vinyl butyl ether-maleic anhydride copolymer, acrylonitrile-methyl methacrylate maleic anhydride copolymer At least one selected from a polymer and a butyl-styrene-maleic anhydride copolymer or the enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate, and polyvinyl acetal phthalate. Preferably, an enteric cellulose derivative, an enteric acrylic acid copolymer, or a mixture thereof can be used, and more preferably, hydroxypropyl methyl cellulose phthalate, methyl methacrylate acrylic acid copolymer, or a mixture thereof can be used.

The water insoluble polymer refers to a polymer that is insoluble in pharmaceutically acceptable water that controls the release of the drug. The water insoluble polymers usable in the present invention are polyvinyl acetate, water insoluble polymethacrylate copolymers (e.g. poly (ethylacrylate-methyl methacrylate) copolymers (e.g. Eudragit NE30D), poly (ethylacrylic) Laminate-methyl methacrylate-trimethylaminoethylmethacrylate) copolymer (e.g. Eudragit RS PO), ethylcellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacyl Latex, cellulose acetate, cellulose diacetate, cellulose triacetate, and mixtures thereof. Preferably cellulose acetate can be used.

The hydrophobic compound refers to a substance that does not dissolve in pharmaceutically acceptable water that controls the release of the drug. The hydrophobic compounds usable in the present invention are selected from the group consisting of fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances, and mixtures thereof, and the fatty acids and fatty acid esters are glyceryl palmitostearate, glycerol. One or more of the fatty acid alcohols selected from among reyl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate, and threaric acid is selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol. At least one selected from carnauba wax, beeswax, and microcrystalline wax, or the inorganic material, is at least one selected from talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, and non-gum. Preferably fatty acids and fatty acid esters can be used, more preferably glyceryl bihenate.

The hydrophilic polymer refers to a polymer dissolved in pharmaceutically acceptable water that controls the release of the drug. The hydrophilic polymer usable in the present invention is selected from the group consisting of sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl polymers, and mixtures thereof, The saccharide is one selected from dextrin, polydextrin, dextran, pectin and pectin derivative, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose, and amylopectin The above cellulose derivative is contained in hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose acetate succinate, and hydroxyethyl methyl cellulose. The at least one gum selected from the group consisting of guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, gum arabic, gellan gum, and xanthan gum is one or more of the proteins selected from gelatin, casein and zein. The polyvinyl derivative is at least one selected from polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl acetal diethylamino acetate, and the hydrophilic polymethacrylate copolymer is poly (butyl methacrylate- (2-dimethylaminoethyl) meth Acrylate-methylmethacrylate) copolymers (eg Eudragit E100, Evonik, Germany), poly (methacrylate-methylmethacrylate) copolymers (eg Eudragit L100), and poly ( One or more of said polyethylene derivatives selected from methacrylic acid-ethylacrylate) copolymers (eg, Eudragit L100-55) are selected from the group consisting of polyethylene glycol, And at least one selected from polyethylene oxide or the carboxyvinyl polymer is a carbomer. Preferably it is a cellulose derivative, a carboxyvinyl polymer, or a mixture thereof, More preferably, hydroxypropylmethylcellulose, a carbomer, or a mixture thereof can be used.

The release controlling substance of the present invention may also preferably use a combination of a water insoluble polymer and a hydrophilic polymer, a combination of an enteric polymer and a hydrophilic polymer, or a combination of an enteric polymer, a hydrophobic compound and a hydrophilic polymer.

(2-2) Osmotic pressure regulator and semipermeable membrane coating base

The delayed-release compartment in the pharmaceutical formulation of the present invention may be a compartment containing an osmotic pressure control agent and coated with a semipermeable membrane coating agent for controlling the release of the active ingredient.

The semi-permeable membrane coating base is a pharmaceutically usable coating base, and refers to a substance used in forming a membrane which is blended into the coating layer of the pharmaceutical formulation and passes some components but does not pass other components. The semipermeable membrane coating base usable in the present invention is polyvinyl acetate, polymethacrylate copolymer, poly (ethylacrylate, methyl methacrylate) copolymer, poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmetha Acrylate) copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, and mixtures thereof Preferably, ethyl cellulose, cellulose acetate, or a mixture thereof can be used.

The semi-permeable membrane coating base may be included in an amount of 0.5 to 10 parts by weight, preferably 1 to 5 parts by weight based on 1 part by weight of amlodipine, and when less than 0.5 parts by weight, the release rate is not controlled. In this case, excessive elution is delayed.

The osmotic pressure control agent refers to a component used to control the release rate of the drug by using the principle of osmotic pressure, the osmotic pressure control agent usable in the present invention is magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, Sodium sulfate, and mixtures thereof, preferably sodium chloride.

Osmotic pressure control agent may be included in 0.5 to 10 parts by weight, preferably 2 to 5 parts by weight with respect to 1 part by weight of amlodipine, if less than 0.5 parts by weight osmotic pressure generation effect is weak, if more than 10 parts by weight There is a problem that unnecessarily increase the total weight of the formulation or achieve a suitable drug release rate.

(3) pharmaceutically acceptable additives

Delayed-release compartments may also be formulated to include additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, pH adjusters, antifoams, dissolution aids, surfactants, and the like, without departing from the effects of the present invention.

The diluents, binders, disintegrants, lubricants, pH adjusting agents, dissolution aids and surfactants may be used as mentioned in the "1.

The antifoaming agent may be used such as dimethicone (dimethicone), oleyl alcohol, propylene glycol alginate, simethicone such as simethicone emulsion.

In addition, the formulation of the present invention may be formulated by using pharmaceutically acceptable additives as various additives selected from colorants and fragrances.

The additive usable in the present invention is not limited to the above additives. The additives may be formulated to contain a range of usual doses by selection.

The pharmaceutical preparations of the present invention can be prepared in a variety of formulations and can be formulated, for example, in tablets, powders, granules, capsules, and the like, such as uncoated tablets, coated tablets, multilayer tablets, or nucleated tablets.

The pharmaceutical formulation of the present invention may be in the form of a two-phase matrix tablet prepared after mixing the delayed-release compartment and the prior-release compartment.

In addition, the pharmaceutical formulation of the present invention may be in the form of a film coated tablet consisting of a tablet consisting of a delayed-release compartment and a film coating layer consisting of a pre-release compartment surrounding the outside of the tablet, the film coating layer of the film coating layer as it is dissolved Valsartan will be eluted first.

In addition, the pharmaceutical formulation of the present invention is obtained by mixing the pharmaceutical additives in the granules constituting the delayed-release compartment and the prior-release compartment, and tableting each tablet in parallel or triplet tablets using multiple tableting machines. The release compartment and the pre-release compartment may be in the form of a multi-layered tablet that forms a multilayer structure. This formulation is a tablet for oral administration which is formulated to enable pre-release and delayed release in layers.

In addition, the pharmaceutical formulation of the present invention may be in the form of a nucleus tablet consisting of an inner core consisting of a delayed-release compartment and an outer layer consisting of a prior-release compartment surrounding the outer surface of the inner core. The nucleated tablet may be an osmotic nucleated tablet, and the osmotic nucleated tablet contains an osmotic pressure regulator within the tablet for delayed release, followed by tableting, followed by coating the surface of the tablet with a semipermeable membrane coating agent to make it an inner nuclear tablet. It is a formulation having a delayed-release inner core prepared by mixing the granules constituting the pre-release compartment with a pharmaceutical additive and then tableting it as an outer layer and having a pre-release outer layer surrounding the surface of the inner core.

Pharmaceutical formulations of the invention may be in the form of particles, granules, pellets, or tablets comprising delayed-release compartments, or capsules comprising particles, granules, pellets, or tablets, consisting of pre-release compartments.

The pharmaceutical formulation of the present invention may further have a coating layer on the outside of the delayed-release compartment and the prior-release compartment. In other words, the surface of the particles, granules, pellets, tablets and the like consisting of the delayed-release compartment and the prior-release compartment may be coated for the purpose of controlling the release or stabilizing the formulation.

In addition, the pharmaceutical preparation of the present invention may be in the form of a kit comprising a delayed-release compartment and a prior-release compartment, and specifically, the present invention prepares particles, granules, pellets, or tablets constituting the prior-release compartment, The granules, pellets or tablets constituting the delayed-release compartment may be separately prepared, and may be in the form of a kit prepared in a form that can be taken at the same time by filling together with a foil, a blister, a bottle, and the like.

The kit may consist of a unit dosage form of a delayed-release compartment, a unit dosage form of a prior release compartment, and a packaging container for packaging the unit dosage forms of the delayed release compartment and the prior release compartment, wherein the packaging container may be a Each of the unit dosage form and the unit dosage form of the prior release compartment may be packed separately or together.

The pharmaceutical preparations according to the present invention may be provided in the form of uncoated tablets without additional coating, but may be in the form of coated tablets which further include a coating layer by forming a coating layer on the outside of the preparation, if necessary. By forming the coating layer, it is possible to provide a formulation capable of further securing the stability of the active ingredient.

The method of forming the coating layer may be appropriately selected by a person skilled in the art from the method of forming a film-like coating layer on the surface of the tablet layer, a method such as a fluidized bed coating method, a fan coating method may be applied, and preferably Fan coating can be applied.

The coating layer may be formed using a coating agent, a coating aid, or a mixture thereof. Specifically, the coating agent may be a cellulose derivative such as hydroxypropylmethylcellulose, hydroxypropylcellulose, sugar derivatives, polyvinyl derivatives, waxes, fats, gelatin, or the like. Or a mixture thereof, and the like, and a coating aid may be polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, talc, diethyl phthalate, a mixture thereof, or the like.

The coating layer may comprise 0.5 to 15% by weight relative to the total weight of the tablet.

Pharmaceutical formulations of the invention may be for evening administration. That is, by taking the preparation of the present invention once a day, especially in the evening (17 to 23 o'clock), effectively lowering blood pressure until dawn by valsartan released, effectively lowering blood pressure after dawn by amlodipine delayed release. It will be 24 hours equal anti-pressure action and prevent complications.

In particular, blood pressure can be maintained evenly during the risk of complications (from dawn to morning time), so hypertensive patients with complications such as patients with hypertension, such as senile hypertension, should be suppressed over 24 hours. Useful. In addition, unlike general hypertension patients, it is useful for suppressing non-dipper type hypertension, a type of hypertension in which blood pressure does not decrease during sleep. The non-dipper type hypertension is present in the elderly, diabetics, cardiac hypertrophy, and high blood pressure with a high risk of complications such as stroke. In other words, taking the formulation of the present invention in the evening time can effectively suppress blood pressure during sleep.

The present invention provides a method for treating cardiovascular disease, comprising administering the delayed-release preparation of the present invention to a mammal. The cardiovascular disease includes all of the hypertension and complications of those with metabolic syndrome, such as hypertension or diabetes, obesity, hyperlipidemia, coronary artery disease, etc., chronic stable angina pectoris, vascular spasms, stroke, myocardial infarction , Transient ischemic attack, congestive heart failure, insulin resistance, impaired glucose tolerance, prediabetes, type 2 diabetes mellitus, diabetic nephropathy, dyslipidemia, cognitive decline and dementia.

The pharmaceutical preparations of the present invention may be formulated using methods disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA, as appropriate methods in the art, and specifically, in the following steps You can.

The first step is to mix, granulate, or coat amlodipine by administering one or two or more release control substances selected from enteric polymers, water insoluble polymers, hydrophobic compounds, and hydrophilic polymers with conventional additives used in pharmaceuticals. Obtaining delayed-release granules or tablets.

When the osmotic pressure control agent and the semipermeable membrane coating agent are used as the delayed-release compartment, mixing, association, drying, granulation, or tableting by administering amlodipine, the osmotic pressure control agent, and a pharmaceutically usable additive, and then coating and delaying the coating with the semipermeable membrane coating agent Prepare release granules or tablets.

The second step is to obtain the prior-release granules or tablets through conventional procedures for producing oral solids such as valsartan by mixing, associating, drying and granulating with conventional pharmaceutically acceptable additives.

In the third step, the granules or tablets obtained in the first step and the second step are mixed with pharmaceutical excipients, tableted or filled to obtain a preparation for oral administration.

The first step and the second step may be reversed or executed simultaneously.

The composite formulation of the present invention may be prepared by the above process, and the formulation method is described in more detail as follows, but is not limited thereto.

[A] Preparation of two-phase matrix tablet

The tablets are prepared by further coating the particles or granules obtained in the first step as they are or with a time-release material, then mixing with the granules prepared in the second step and tableting to a certain amount of weight. The obtained tablet can be film coated as necessary for the purpose of improving stability or property.

[B] Preparation of Film-Coated Tablets Containing Active Ingredients

The coated tablets or granules obtained in the first step are additionally coated as they are or with a release control material, dried, and then compressed into a predetermined amount to prepare tablets as they are or additionally prepared, and then valsartan is separately dissolved or dispersed in an aqueous film coating solution. After the coating on the outer layer of the tablet obtained in the first step it can be prepared orally administered film coating tablet containing the active ingredient in the film coating.

Preparation of multi-layered tablets

The granules obtained in the first step may be further coated as they are or with a release control material, and the dried granules and the granules obtained in the second step may be added to produce double tablets using a multi-layer tablet press. Coated multi-layered tablets can be prepared by formulating or coating triple or more multi-layered tablets by adding a release aid layer as needed, or by formulation design.

[D] Preparation of Nucleated Tablets

The coated tablet or granules obtained in the first step are additionally coated as it is or with a release control material, dried, and then compressed into a predetermined amount to be coated as it is or additionally to the inner core, and then with the granules obtained in the second step, The coated nucleated tablet may be prepared by preparing or coating a nucleated tablet in a form in which a pre-release layer surrounds the surface of the first-stage tablet.

[E] Preparation of Capsules (Granules or Tablets)

The granules obtained in the first step are additionally coated as it is or with a release controlling substance, and the dried granules or tablets and the granules or tablets obtained in the second step are placed in a capsule charger and filled into capsules of a predetermined size by an effective amount of each active ingredient in an appropriate amount. Can be prepared.

[Bar] Preparation of capsules (pellets)

(1) Dissolve or suspend amlodipine and release control substances or pharmaceutically acceptable additives in water, organic solvents or mixed solvents to coat the spherical granules of sugar, and then dry the time release alone or two or more as necessary. After dissolving in water, an organic solvent, or a mixed solvent, coating, drying, and then mixed with the granules obtained in the second step or tablets obtained in the third step and filled into capsules to prepare a capsule.

(2) Dissolve or suspend cetvalsartan and a pharmaceutically acceptable additive in water, an organic solvent, or a mixed solvent, coat the spherical granules with sugar, dry them, mix them with delayed-release pellets containing amlodipine in the defroster, Capsules can be prepared by filling.

[Product] Kit Preparation

The amlodipine-containing preparation obtained in the first step and the valsartan-containing preparation obtained in the second step may be filled together in a foil, blister, bottle, or the like to prepare a kit that can be taken at the same time.

The human dosage of the pharmaceutical formulation of the present invention is appropriately selected according to the absorption rate, inactivation rate and excretion rate of the active ingredient in the body, the age, sex and condition of the patient, but generally in the total amount of amlodipine and valsartan in adults, 2.0 to 840 mg per day, preferably 22 to 660 mg per day can be exerted anti-pressure action and prevent complications.

The pharmaceutical formulation of the present invention is formulated to be compatible with the principle of time lag by allowing time lag between two components of valsartan and amlodipine, which increases the efficacy and side effects compared to the case where the two drugs are simultaneously released. Can be reduced.

In other words, the pharmaceutical preparation of the present invention may exhibit the most ideal effect when the drug is released in the body at a specific rate by applying the Chronotherapeutics principle to express the optimal pharmacological action of each pharmacologically active ingredient. Is a drug delivery system designed to be.

The pharmaceutical preparation of the present invention exhibits an equal anti-pressure action and prevents complications, and is particularly useful for hypertension patients with complications, suppressing blood pressure during sleep, and at the same time, which can maintain blood pressure evenly during the risk of complications. Because it can be taken, it is easy to guide and take the medication for the patient.

Hereinafter, the present invention will be described in detail with reference to Examples, but the scope of the present invention is not limited to these Examples.

Example 1 Preparation of Amlodipine / Valsartan Two-Phase Matrix Tablets

(1) Preparation of Valsartan Pre-Release Granules

Valsartan (Dr Reddy's, India), lactose (Parmatose, DMV Pharma, Netherlands), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA) and poloxamer 188 (Lutrol-F68, BASF, Germany) were used as the ingredients and contents shown in Table 1. Weighed apples in No. 35 sieve and mixed for 15 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The mixture was put into a fluidized bed granulator and granulated by the addition of a binder solution. High speed mixers are optionally used in the assembly process. The fluidized bed granulator was a top-spray system using GPCG-1 (Glatt, Germany). After the granules were added, they were preheated under the following conditions. The air flow was 80 m ³ / hour, the inlet air temperature was 40 ° C, and the filter shaking (delta P filter <500pa) was performed in asynchronous mode for 5 seconds in 30 seconds. When the product temperature reached 35 ° C. in the preheating process, the binder was sprayed at 1.0 to 10 g per minute, granulated and sprayed (atomizing air) was adjusted in the range of 1.0 to 2.0 bar and the coating liquid spray angle was adjusted. Air flow increases from 80 m ³ / h to 120 m ³ / h as the process proceeds, and the filter shaking (delta P filter <4000 pa) is kept in concurrency mode in 1 minute to prevent loss. It was assembled while performing for 5 seconds.

After the assembly was completed, the granules were dried in a fluid bed granule dryer.

GPCG-1 (Glatt, Germany) was used for the fluid bed granule dryer, and the granulation was carried out under the following conditions. The air flow was 120 m ³ / hour, the inlet air temperature was 65 ° C, and the filter shaking (delta P filter <4000 pa) was performed in asynchronous mode for 5 seconds in 30 seconds. When the product temperature reaches 40 ℃, the sample was taken and completed if it meets the criteria of 2.5% or less of drying loss, and if it exceeds, it proceeds further and re-measures to complete drying.

When the drying was completed, the dried product was established using a No. 20 sieve equipped with an F-type granulator, the mixture was placed in a double cone mixer, magnesium stearate was added and mixed for 4 minutes to prepare valsartan pre-release granules.

(2) Preparation of delayed-release granules of amlodipine

As shown in Table 1, amlodipine besylate (Cadila, India), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), crosslinked polyvinylpyrrolidone (Crospovidone, BASF, Germany), croscarmellose sodium ( Vivasol, JRS Pharma, Germany) was appled with No. 35 sieve and mixed for 5 minutes with a double cone mixer. A hydroxypropyl cellulose (HPC-L, Nippon soda, Japan) was separately dissolved in purified water to prepare a binding solution. The conditions of the fluid bed granulator and fluid bed drying are the same as those of valsartan pre-release granules. The dried material is placed in a fluid bed coater, and separately the cellulose acetate (acetal group 32%) (Eastman Chemical Company, USA), the cellulose acetate (acetal group 39.8). %) (Eastman Chemical Company, USA), a solution of hydroxypropylmethylcellulose dissolved in ethanol and methylene chloride was prepared and the granulated material was put into a fluidized bed granulator coater and coated.

The fluid bed granulation coater used the GPCG-1 (Glatt, Germany) bottom-spray system. The plate to be adjusted according to the size of the granule is B or C type, the partition gap is 25 mm, spraying The nozzle was mounted with a size of 1 mm. After the granulation, the air flow was 100 m ³ / hour, inlet air temperature was 45 ~ 60 ℃, product temperature was 40 ~ 50 ℃, filter shaking ( The delta P filter (maintained at <500 pa) was run for 5 seconds in 30 seconds in asynchronous mode. When the product temperature reached 35 ° C in the preheating process, the film coating liquid was sprayed at 1 to 5 g / min and the coated air ( atomizing air) was controlled in the range of 1.0 to 1.5 bar, and the coating liquid spray angle was controlled. During the process, the product temperature was maintained at 34 to 38 ℃, and after the coating was completed, the product temperature was maintained at 40 ℃ for about 1 hour. The degree of drying and surface work. After completion of putting the amlodipine was prepared delayed-release granules by mixing for 4 minutes and then the magnesium stearate added.

(3) tableting and coating

The two granules of (1) and (2) were mixed and compressed in a rotary tablet press (MRC-33: Sejong Machinery, Korea). Once tablets have been tableted, hydroxypropylmethylcellulose 2910 (Shin-etsu, Japan), polyethylene glycol 6000 (BASF, Germany), and titanium oxide (Tioside Americas, USA) are dissolved and dispersed in ethanol and purified water in the amounts shown in Table 1. After coating using the prepared coating solution to prepare a two-phase matrix tablet.

Example 2 Preparation of Amlodipine / Valsartan Double Tablet

The amlodipine delayed-release granules prepared according to the method described in (1) of Example 1 and the valsartan pre-release granules prepared according to the method described in (1) of Example 1 with the components and contents shown in Table 1 were used. After tableting in the granule inlet of the triple tablet press (MRC-37T: Sejong Machinery, Korea), the tablets with the tablets were hydroxypropylmethylcellulose 2910, polyethylene glycol 6000, and titanium oxide. To prepare a double tablet by coating using a coating solution prepared by dissolving and dispersing in purified water.

Example 3 Preparation of Amlodipine / Valsartan Multi-Layered Tablet

The amlodipine delayed-release granules prepared according to the method described in (1) of Example 1 with the ingredients and contents shown in Table 1 were stacked in an intermediate layer (second layer), and according to the method described in (1) of Example 1 The valsartan pre-release granules thus prepared were divided into 1 and 3 layers, respectively, placed in different granule inlets of the rotary triple tablet press (MRC-37T: Sejong Machinery, Korea), and then compressed into tablets. By using a coating solution prepared by dissolving and dispersing hydroxypropyl methyl cellulose 2910, polyethylene glycol 6000, titanium oxide in ethanol, purified water to prepare a multilayer tablet.

Example 4 Preparation of Amlodipine / Valsartan Nucleus Tablets

After the inner core was prepared by compressing the amlodipine delayed-release granules prepared according to the method described in (2) of Example 1 with a rotary tablet press (MRC-33: Sejong Machinery, Korea) with the ingredients and contents shown in Table 1. After tableting with valsartan pre-release granules prepared according to the method described in (1) of Example 1 in a nucleation tableting machine (RUD-I: Kilian, Germany), the tablets to which tableting is completed are hydrated to the contents shown in Table 1. The nucleophilic tablet was prepared by coating with a coating solution prepared by dissolving and dispersing oxypropylmethylcellulose 2910, polyethylene glycol 6000, and titanium oxide in ethanol and purified water.

Example 5 Preparation of Amlodipine / Valsartan Capsule (Tablet + Tablet)

(1) Preparation of Valsartan Delayed-Release Tablet

Prepared according to the preparation method described in (1) of Example 1 with the ingredients and contents shown in Table 1, by delaying the valsartan release by granulating the valsartan layer pre-release granules in a rotary tablet press (MRC-33: Sejong Machinery, Korea) Sex tablets were prepared.

(2) Preparation of amlodipine delayed-release tablets

In the ingredients and contents shown in Table 1, amlodipine besylate and microcrystalline cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium were apples in No. 35, mixed in a double cone mixer, and then mixed in a fluidized bed granulator (GPCG 1: Glatt). It was added and sprayed with a bonding liquid prepared by dissolving hydroxypropyl cellulose in water, and granules were formed and dried. Carbomer 71G (carboxyvinyl polymer, Lubrizol) was added to the granules in a powder state, mixed for 10 minutes, and then sieved to a constant size. Magnesium stearate was added thereto, mixed with a final double cone mixer, and the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong Machinery) to prepare uncoated tablets. Separately, hydroxypropylmethylcellulose phthalate was dissolved in 80% ethanol to prepare a coating solution, and then the tablets were administered to a fluidized bed coater and coated to prepare amlodipine delayed-release tablets.

Capsules were prepared by filling two capsules prepared above into capsules.

Example 6 Preparation of Amlodipine / Valsartan Capsules (Tablets + Granules)

After preparing amlodipine delayed-release tablets according to the method described in (2) of Example 5 with the ingredients and contents shown in Table 1, and preparing valsartan pre-release granules according to the method described in (1) of Example 1, Each tablet and granules were filled into the same capsule to prepare amlodipine / valsartan capsules (tablets + granules).

Example 7 Preparation of Amlodipine / Valsartan Capsules (Granules + Granules)

The capsules were prepared by filling the capsules with amlodipine delayed-release granules and valsartan pre-release granules prepared according to the preparation method described in Example 1 with the ingredients and contents shown in Table 1.

Example 8 Preparation of Amlodipine / Valsartan Capsule (Pellets + Pellets)

(1) Preparation of Valsartan Prior-Release Pellets

 After sieving the sugar sphere (Sugar sphere) with a No. 35 sieve with the ingredients and contents shown in Table 1, and putting it in a fluidized bed granulator (GPCG 1: Glatt), hydroxypropyl cellulose (HPC-L, Nippon soda) in water and ethanol separately , Japan), valsartan, and poloxamer 188 were sprayed with a binding solution that was dissolved or suspended to form pellets containing valsartan and dried to prepare valsartan pre-release pellets.

(2) Preparation of Amlodipine Delayed-Release Pellets

The sugar spheres were sieved through a No. 35 sieve with the ingredients and contents shown in Table 1, added to a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose and amlodipine besylate were dissolved separately in water and ethanol or The suspension binding solution was sprayed to form amlodipine containing pellets and dried. The granules were sprayed with hydroxypropyl methyl cellulose phthalate in 200 mg of ethanol and 100 mg of methylene chloride to prepare amlodipine delayed-release pellets.

Two prepared pellets were mixed and filled into capsules to prepare capsules.

Example 9 Preparation of Amlodipine / Valsartan Capsules (Tablets + Pellets)

With the ingredients and contents shown in Table 1, valsartan pre-release pellets were prepared in the same manner as described in (1) of Example 8, and according to the preparation method described in (2) of Example 5, amlodipine delayed-release property Tablets were prepared and prepared by filling the capsules with the prepared tablets and pellets.

Example 10 Preparation of Ummarodipine / Valsartan Two-Phase Matrix Tablets

(1) Preparation of Valsartan Pre-Release Granules

Valsartan, lactose, poloxamer 188, microcrystalline cellulose, sodium starch glycolate were weighed into apples No. 35 with ingredients and contents shown in Table 1, and mixed for 20 minutes in a double cone mixer to prepare a mixture. After completion of mixing, magnesium stearate was added and mixed for 4 minutes to prepare valsartan pre-release granules.

(2) Preparation of amlodipine delayed-release granules

Amlodipine besylate, microcrystalline cellulose, croscarmellose sodium, cross-linked polyvinylpyrrolidone and apples in No. 35 were mixed with the ingredients and contents shown in Table 1 and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to obtain a binding solution. After the above mixture was administered to a fluidized bed granulator or a high speed mixer, the binder was sprayed to prepare granules. After the granules were dried in a fluidized bed dryer, Compritol 888 ATO (Glyceryl Bihenate, Gattefose) was added to the granules in a powder state, mixed for 10 minutes, and sieved to a constant size. Separately, a solution of hydroxypropylmethylcellulose dissolved in purified water and acrylics (Acryl-eze, Colorcon, USA) were dissolved in 80% ethanol to prepare a coating solution. After the preparation of the coating solution was completed, the granules were administered to a fluidized bed coater and subjected to a primary coating (hydroxypropylmethylcellulose coating solution), followed by a secondary coating (acrylic coating solution). After completion of the coating, after adding magnesium stearate and mixing for 4 minutes to prepare amlodipine delayed-release granules.

(3) tableting and coating

The two granules were mixed and compressed in a rotary tablet press (MRC-33: Sejong Machinery, Korea). Tablets, which have been tableted, are coated with hydroxypropylmethylcellulose 2910, polyethyleneglycol 6000, and titanium oxide with a coating solution dissolved and dispersed in ethanol and purified water in the contents shown in Table 1, thereby preparing a biphasic matrix tablet.

Example 11 Preparation of Amlodipine / Valsartan Blister Packaging Kit

(1) Valsartan prior-release tablet preparation

Weigh valsartan, lactose, poloxamer 188, microcrystalline cellulose, pregelatinized starch (Starch 1500G, Colorcon, USA) with the ingredients and contents shown in Table 1, apples with No. 35 sieve, and mix in a double cone mixer for 20 minutes. Was prepared. After completion of mixing, magnesium stearate was added and mixed for 4 minutes to prepare valsartan pre-release granules.

The valsartan pre-release granules prepared according to the above method were compressed into tablets using a rotary tablet press (MRC-33: Sejong Machinery, Korea).

The prepared tablets were coated with a coating solution in which hydroxypropylmethylcellulose 2910, polyethylene glycol 6000, and titanium oxide were dissolved and dispersed in ethanol and purified water in the amounts shown in Table 1.

(2) Preparation of amlodipine delayed-release tablets

According to the ingredients and contents shown in Table 1, according to the preparation method described in (2) of Example 5, amlodipine delayed-release tablets were prepared.

(3) packing kit manufacturing

Each coated tablet was packaged in one PTP (Press Through Pack) packaging container to prepare a packaging kit that can be used at the same time.

Example 12 Preparation of Amlodipine / Valsartan-Containing Film-Coated Tablets

(1) Preparation of Valsartan Coating Liquid

In the ingredients and contents shown in Table 1, valsartan, a colloidal silicon oxide, poloxamer 188, and hydroxypropyl cellulose were dissolved in a mixture of ethanol and purified water to prepare a valsartan coating solution.

(2) Preparation of amlodipine delayed-release tablet

With the ingredients and contents shown in Table 1, amlodipine besylate, microcrystalline cellulose, croscarmellose sodium, cross-linked polyvinylpyrrolidone were apples in No. 35, mixed in a double cone mixer, and then mixed in a fluidized bed granulator (GPCG 1: Glatt). It was added and sprayed with a bonding liquid prepared by dissolving hydroxypropyl cellulose in water, and granules were formed and dried. Carbomer 71G was added to the granules in a powder state and mixed for 10 minutes. Magnesium stearate was added thereto and mixed with a final double cone mixer. The final mixture was crushed with a rotary tablet press (MRC-33: Sejong Machinery). Uncoated tablets were prepared.

Separately, a solution of hydroxypropylmethylcellulose dissolved in purified water and acrylics (Acryl-eze, Colorcon, USA) were dissolved in 80% ethanol to prepare a coating solution. After the preparation of the coating solution was completed, the tablet was administered to the coating machine and the first coating (hydroxypropylmethylcellulose coating solution), and then the secondary coating (acrylic coating solution).

(3) coating

The amlodipine tablets prepared above were administered to a high coater (SFC-30N, Sejong Machinery, Korea) and coated with Valsartan coating solution. After the drug coating was completed, hydroxypropylmethylcellulose 2910, polyethylene glycol 6000, and titanium oxide were coated with ethanol and a coating solution dissolved and dispersed in purified water in the contents shown in Table 1 to prepare a film coated tablet.

Example 13 Preparation of Amlodipine / Valsartan Osmotic Nucleated Tablets

(1) Preparation of Valsartan prior-release granules

Weigh valsartan, lactose, poloxamer 188, microcrystalline cellulose, pregelatinized starch (Starch 1500G, Colorcon, USA) with the ingredients and contents shown in Table 1, apples with No. 35 sieve, and mix in a double cone mixer for 20 minutes. Was prepared. After completion of mixing, magnesium stearate was added and mixed for 4 minutes to prepare valsartan pre-release granules.

(2) Preparation of amlodipine delayed-release nuclear tablets (inner core)

According to the ingredients and contents of Table 1, amlodipine besylate, microcrystalline cellulose, croscarmellose sodium, cross-linked polyvinylpyrrolidone and sodium chloride were apologized with No. 35 sieve, mixed with a double cone mixer, and magnesium stearate was added thereto. The mixture was mixed with a cone mixer, and the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong Machinery). After tableting, ethyl cellulose was dispersed in purified water as a semipermeable membrane coating base, and then coated with an inner core using a high coater (SFC-30N, Sejong Machinery, Korea) to prepare an osmotic core tablet.

(3) tableting and coating

Using a nucleated tablet tablet press (RUD-1: Kilian) as an inner core of the amlodipine osmotic core tablet and valsartan pre-release granules as the outer layer, the tablets were compressed and a film coating layer was formed using a high coater (SFC-30N, Sejong Machinery, Korea). Nucleated tablets were prepared. Tablets, which have been tableted, are coated with a hydroxypropylmethylcellulose 2910, polyethylene glycol 6000, and titanium oxide dissolved in ethanol and purified water to a content shown in Table 1 to prepare an osmotic nucleus.

Example 14 Preparation of Amlodipine / Valsartan Two-Phase Matrix Tablets

(1) Preparation of Valsartan prior-release granules

With the components and contents of Table 2, valsartan pre-release granules were prepared according to the preparation method described in (1) of Example 1.

(2) Preparation of delayed-release granules of amlodipine

Amlodipine delayed-release granules were prepared according to the preparation method described in (2) of Example 1, except that amlodipine maleate was used as the pharmacologically active ingredient as the ingredients and contents of Table 2.

(3) tableting and coating

With the ingredients and contents of Table 2, tablets were compressed and coated according to the method described in Example 1 (3) to prepare two-phase matrix tablets.

Example 15 Preparation of Amlodipine Valsartan Double Tablet

Amlodipine / Valsartan double tablets were prepared according to the preparation method described in Example 2, except that amlodipine maleate was used as the pharmacologically active ingredient as the ingredients and contents of Table 2.

Example 16 Preparation of Amlodipine / Valsartan Capsule (Pellets + Pellets)

Amlodipine / Valsartan capsules were prepared according to the preparation method described in Example 8, except that amlodipine maleate was used as the pharmacologically active ingredient as the ingredients and the contents of Table 2.

Example 17 Preparation of Amlodipine / Valsartan Multi-Layered Tablet

Amlodipine / Valsartan multi-layered tablets were prepared according to the preparation method described in Example 3, except that (S) -amlodipine besylate was used as the pharmacologically active ingredient.

Example 18 Preparation of Amlodipine / Valsartan Capsule (Tablet + Tablet)

According to the ingredients and contents of Table 2, according to the preparation method described in Example 5, amlodipine / valsartan capsules were prepared.

Example 19 Preparation of Zamodidipine / Valsartan Two-Phase Matrix Tablets

With the ingredients and contents of Table 2, amlodipine / valsartan biphasic matrix tablets were prepared according to the preparation method described in Example 10.

Experimental Example 1 Dissolution Profile Test

Comparative elution using Valsartan mono (Diovan, Novartis) and Amlodipine Besylate mono (Novask, Novartis) as tablets and control formulations of Examples 1, 9 and 12 as the test formulation of the present invention The test was carried out, and the experimental results are shown in FIGS. 1 and 2. The valsartan dissolution test was carried out based on the U.S. Pharmacopoeia (USP 31), and the amlodipine dissolution test was changed from 0.1 N hydrochloric acid (acidic environment) to pH 6.8 (phosphoric acid solution) buffer for 2 hours. The experiment was carried out (the test population was 12 each).

[Valsartan Test Method]

Dissolution test basis: 'Valsartan and Hydrochlorothiazide tablet' in USP 31

Test method: Paddle method, 50 revolutions / minute

Test solution: pH = 6.8 buffer (phosphate solution), 1000 mL

Analytical Method: Ultraviolet-visible Spectrophotometry (Detect Wavelength = Max 270, Min 250 nm)

[Amlodipine Test Method]

Dissolution test basis: 'Amlodipine Besylate / Valsartan Tablet' in Dissolution Methods for Drug Products (FDA)

Test method: Paddle method, 50 revolutions / minute

Test solution: 0.1 N hydrochloric acid solution, 500 mL (0-2 hours),

pH 6.8 artificial intestine, 900 mL (after 2 hours)

Analytical Method: Ultraviolet-visible Spectrophotometry (Detect Wavelength = 237 nm)

As shown in Figures 1 and 2, the valsartan component shows almost the same elution characteristics as the control agent Diovan, but the amlodine component shows a very slow dissolution rate when compared to the control formulation Novasque. Specifically, comparing the dissolution results of the amlodipine component, the valsartan / amlodipine formulation of the present invention can be confirmed that the dissolution rate of the amlodipine component is less than 10% to 120 minutes, the artificial gastric juice interval, the control agent is about 99%.

That is, as shown in Figures 1 and 2, it can be seen that the pharmaceutical formulation of the present invention releases the valsartan component by more than 90% within about 30 minutes, and delays the release of the amlodipine component by about 120 minutes or more. Therefore, the time-release effect of the valsartan component and the amlodipine component of the pharmaceutical formulation of the present invention can be confirmed.

Experimental Example 2 Dissolution Profile Test

As the experimental preparation of the present invention, a comparative dissolution test was performed using valsartan / amlodipine simple combination (Exforge, manufactured by Novartis) as a tablet and a control formulation of various formulations obtained in Examples 1, 2, 4, 5, and 11, The results are shown in FIGS. 3, 4 and 5. Dissolution test method is the same as Experimental Example 1.

[Valsartan Test Method]

Dissolution test basis: 'Valsartan and Hydrochlorothiazide tablet' in USP 31

Test method: Paddle method, 50 revolutions / minute

Test solution: pH = 6.8 buffer (phosphate solution), 1000 mL

Analytical Method: Ultraviolet-visible Spectrophotometry (Detect Wavelength = Max 270, Min 250 nm)

As shown in Figures 3 and 4, the valsartan / amlodipine simple combination formulation releases both the valsartan component and the amlodipine component by more than 90% within 20 minutes, whereas the pharmaceutical formulation of the present invention releases the valsartan component within about 30 minutes. It can be seen that the release of more than 90%, delaying the release of the amlodipine component by about 120 minutes or more.

Thus, it can be seen that time release of valsartan and amlodipine is possible only by controlled release pharmaceutical formulations of the present invention.

Through the above comparative dissolution test results, when the tablet prepared in the embodiment of the present invention is administered in the evening time, valsartan is eluted first in the body to regulate blood pressure during the night time, and amlodipine is eluted after several hours, during the day time. It can be seen that blood pressure can be controlled.

In addition, through the experimental example, even if the oral administration form is different, the variation in the dissolution rate of amlodipine is not large, it can be confirmed that the pharmaceutical formulation of the present invention can be prepared in all formulations of the examples.

1 is a graph comparing the dissolution of Example 1 according to Experimental Example 1 and the valsartan single agent and the amlodipine single agent.

Figure 2 is a graph comparing the dissolution of Example 9,12 according to Experimental Example 1 and valsartan single agent and amlodipine single agent.

Figure 3 is a graph comparing the dissolution of valsartan in Example 1 according to Experimental Example 2 and valsartan / amlodipine simple combination formulation.

Figure 4 is a graph comparing the dissolution of Examples 2, 4 and Valsartan / amlodipine simple combination preparation according to Experimental Example 2.

Figure 5 is a graph comparing the dissolution of Examples 5, 11 and Valsartan / amlodipine simple combination preparation according to Experimental Example 2.

Claims (35)

A prior release compartment comprising at least one selected from valsartan, a pharmaceutically acceptable salt thereof, or an isomer thereof as a pharmacologically active ingredient, and amlodipine, a pharmaceutically acceptable salt thereof, or a pharmacologically active ingredient thereof. A pharmaceutical formulation comprising a delayed-release compartment comprising at least one member selected from isomers. The pharmaceutical formulation of claim 1, wherein the valsartan of the prior-release compartment releases at least 85% of the total amount of valsartan within one hour after its release. The pharmaceutical formulation of claim 1, wherein the amlodipine is released 1 hour to 4 hours after the onset of valsartan release. 4. The pharmaceutical formulation of claim 3, wherein the amlodipine is released 1 hour to 2 hours after the onset of valsartan release. The pharmaceutical formulation of claim 1, wherein the delayed-release compartment comprises a release controlling substance selected from the group consisting of enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic polymers, and mixtures thereof. 6. The pharmaceutical formulation of claim 5, wherein the release controlling substance is included in an amount of 0.1 to 100 parts by weight based on 1 part by weight of amlodipine. 6. The pharmaceutical formulation of claim 5 wherein the enteric polymer is selected from the group consisting of enteric cellulose derivatives, enteric acrylic acid copolymers, enteric maleic acid copolymers, enteric polyvinyl derivatives, and mixtures thereof. The method of claim 7, wherein the enteric cellulose derivative is hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzo One or more of the enteric acrylic acid copolymers selected from among ate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethylethyl cellulose and ethyl hydroxyethyl cellulose phthalate are styrene-acrylic acid copolymers, methyl acrylate-acrylic acid copolymers, methyl acrylate. Methacrylic acid copolymer, butyl acrylate-styrene-acrylic acid copolymer, methacrylic acid-methyl methacrylate copolymer, methacrylic acid and ethyl acrylate And at least one of the enteric maleic acid copolymers selected from the group consisting of a sieve and methyl acrylate-methacrylic acid-octyl acrylate copolymer, vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinyl Selected from methyl ether maleic anhydride copolymer, ethylene maleic anhydride copolymer, vinyl butyl ether maleic anhydride copolymer, acrylonitrile-methyl acrylate maleic anhydride copolymer, and butyl styrene-maleic anhydride copolymer At least one or the enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate, and polyvinyl acetal phthalate. 6. The method of claim 5, wherein the water insoluble polymer is polyvinyl acetate, water insoluble polymethacrylate copolymer, poly (ethylacrylate-methyl methacrylate) copolymer, poly (ethylacrylate-methyl methacrylate-trimethyl Aminoethyl methacrylate) copolymer, ethylcellulose, cellulose acetate, and mixtures thereof. The pharmaceutical formulation of claim 5, wherein the hydrophobic compound is selected from the group consisting of fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances, and mixtures thereof. The fatty acid and fatty acid ester according to claim 10, wherein the fatty acid and fatty acid esters are at least one selected from glyceryl palmitostearate, glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and sleanic acid. One or more selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol, the one or more waxes selected from carnauba wax, beeswax, and microcrystalline wax, or the inorganic substance is talc, precipitated calcium carbonate, calcium monohydrogen phosphate. A pharmaceutical formulation comprising at least one selected from zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and non-gum. The drug of claim 5, wherein the hydrophilic polymer is selected from the group consisting of sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl polymers, and mixtures thereof. Pharmaceutical preparations. The method of claim 12, wherein the saccharide is dextrin, polydextrin, dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose And at least one cellulose derivative selected from amylopectin is hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose sodium, hydroxypropyl methylcellulose, acetate succinate, And at least one of the gums selected from hydroxyethyl methyl cellulose is guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, gum arabic, gellan gum, and xanthan gum. And at least one selected from Jane The polyvinyl derivative is at least one selected from polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl acetal diethylamino acetate. The hydrophilic polymethacrylate copolymer is poly (butyl methacrylate- (2-dimethylaminoethyl) One or more of the polyethylene derivatives selected from methacrylate-methylmethacrylate) copolymer, poly (methacrylate-methylmethacrylate) copolymer, and poly (methacrylate-ethylacrylate) copolymer are polyethylene glycol, And at least one selected from polyethylene oxide or the carboxyvinyl polymer is a carbomer. 6. The pharmaceutical formulation of claim 5 wherein the enteric polymer is selected from hydroxypropylmethylcellulose phthalate, methyl methacrylate acrylic acid copolymer, or mixtures thereof. 6. The pharmaceutical formulation of claim 5 wherein the water insoluble polymer is cellulose acetate. 6. The pharmaceutical formulation of claim 5 wherein the hydrophobic compound is glyceryl bihenate. 6. The pharmaceutical formulation of claim 5 wherein the hydrophilic polymer is selected from hydroxypropylmethylcellulose, carbomer, or mixtures thereof. 6. The pharmaceutical formulation of claim 5, wherein the release controlling substance comprises at least one hydrophilic polymer and at least one selected from an enteric polymer, a water insoluble polymer, or a hydrophobic compound. The pharmaceutical formulation of claim 1, wherein the delayed-release compartment comprises an osmotic pressure regulator and is coated with a semipermeable membrane coating base. 20. The method of claim 19, wherein the semipermeable membrane coating base is polyvinyl acetate, polymethacrylate copolymer, poly (ethylacrylate, methyl methacrylate) copolymer, poly (ethylacrylate, methyl methacrylate, trimethylamino Ethyl methacrylate) copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacelated, cellulose triacetate, and mixtures thereof Pharmaceutical agent selected from the group. 20. The pharmaceutical formulation of claim 19, wherein the osmotic pressure regulator is selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, sodium sulfate, and mixtures thereof. 20. The pharmaceutical formulation of claim 19, wherein the osmotic pressure control agent is sodium chloride and the semipermeable membrane coating base is ethylcellulose. The pharmaceutical formulation of claim 1, wherein the amlodipine comprises 1-40 mg of the formulation. The pharmaceutical formulation of claim 1, wherein the valsartan is comprised between 1 and 800 mg of the formulation. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a biphasic matrix tablet prepared after the delayed-release compartment and the prior-release compartment are mixed. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a film-coated tablet consisting of a tablet consisting of a delayed-release compartment and a film-coating layer consisting of a prior-release compartment surrounding the exterior of the tablet. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a multi-layered tablet in which the delayed-release compartment and the prior-release compartment are layered. The pharmaceutical formulation according to claim 1, wherein the formulation is in the form of a nucleus tablet consisting of an inner core consisting of a delayed-release compartment and an outer layer consisting of a prior-release compartment surrounding an outer surface of the inner core. The pharmaceutical formulation of claim 28, wherein the nucleated tablet is an osmotic nucleated tablet. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a capsule comprising particles, granules, pellets, or tablets consisting of delayed-release compartments, and particles, granules, pellets, or tablets consisting of prior-release compartments. The pharmaceutical formulation of claim 1, further comprising a coating layer on the exterior of at least one of the delayed-release compartment or the prior-release compartment. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a coated tablet further comprising a coating layer on the outside. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a kit comprising a delayed release compartment and a prior release compartment. The pharmaceutical formulation of claim 1, wherein the formulation is for evening administration. 35. The method according to any one of claims 1 to 34, wherein the formulation is hypertension, obesity, hyperlipidemia, coronary artery disease, chronic stable angina, vasospasmodic angina, stroke, myocardial infarction, transient ischemic attack, congestive heart failure, insulin A pharmaceutical formulation for preventing or treating a disease selected from the group consisting of resistance, impaired glucose tolerance, prediabetes, type 2 diabetes mellitus, diabetic nephropathy, dyslipidemia, cognitive decline, dementia, and combinations thereof.

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